Starostik P, Manshouri T, O'Brien S, Freireich E, Kantarjian H, Haidar M, Lerner S, Keating M, Albitar M
Division of Medicine, The University of Texas M.D. Anderson Cancer Center, Houston 77030-4095, USA.
Cancer Res. 1998 Oct 15;58(20):4552-7.
The gene mutated in ataxia telangiectasia, ATM, on human chromosome 11q22-q23 is implicated in cell cycle control and DNA repair. Ataxia telangiectasia patients as well as ATM-deficient mice are immune deficient and develop lymphoproliferative disease. Abnormalities in 11q22.3-q23.1 have also been described in B-cell chronic lymphocytic leukemia (B-CLL). We analyzed B-CLL samples for loss of heterozygosity (LOH) using microsatellite markers located at the ATM (D11S2179), mixed-lineage leukemia (MLL; D11S1356), and BCL1 (D11S987) loci, all of which are located around 11q23. Five (14%) of 36 informative cases showed LOH at the ATM gene, and two of these five cases had LOH at the MLL gene. No LOH was detected at the BCL1 locus, and none of the cases showed LOH at the MLL gene without LOH at the ATM gene. Four of these five cases with LOH at the ATM gene were studied for ATM protein expression by Western blot analysis. All four cases lacked ATM protein. An additional 111 cases of B-CLL were studied for expression of ATM protein by Western blot analysis and RIA. Thirty-eight (34%) of these cases showed ATM levels <50% of that seen in normal lymphoid cells. No morphological or immunophenotypic difference was observed between ATM-deficient B-CLL cases and cases with normal ATM expression. However, patients with ATM deficiency had significantly shorter survival times (35.66 versus 97.3 months; P = 0.003) and more aggressive disease, suggesting that ATM is involved in the leukemogenesis of B-CLL. These data also suggest that the ATM gene may play a role in the reported 11q23 abnormality in B-CLL, which also characterizes an aggressive disease.
共济失调毛细血管扩张症中发生突变的基因ATM位于人类11号染色体q22 - q23区域，与细胞周期调控和DNA修复有关。共济失调毛细血管扩张症患者以及ATM缺陷小鼠存在免疫缺陷，并会发展为淋巴增殖性疾病。11号染色体q22.3 - q23.1区域的异常也在B细胞慢性淋巴细胞白血病（B - CLL）中有所描述。我们使用位于ATM（D11S2179）、混合谱系白血病（MLL；D11S1356）和BCL1（D11S987）基因座的微卫星标记分析了B - CLL样本的杂合性缺失（LOH）情况，所有这些基因座均位于11号染色体q23区域附近。36例信息充分的病例中有5例（14%）在ATM基因处显示杂合性缺失，这5例中的2例在MLL基因处也存在杂合性缺失。在BCL1基因座未检测到杂合性缺失，且没有病例在MLL基因处出现杂合性缺失而在ATM基因处未出现杂合性缺失。对这5例在ATM基因处存在杂合性缺失的病例中的4例进行了蛋白质免疫印迹分析以研究ATM蛋白表达。所有4例均缺乏ATM蛋白。另外对111例B - CLL病例进行了蛋白质免疫印迹分析和放射免疫分析以研究ATM蛋白表达。其中38例（34%）病例的ATM水平低于正常淋巴细胞中所见水平的50%。在ATM缺陷的B - CLL病例与ATM表达正常的病例之间未观察到形态学或免疫表型差异。然而，ATM缺陷的患者生存时间显著缩短（35.66个月对97.3个月；P = 0.003）且疾病更具侵袭性，这表明ATM参与了B - CLL的白血病发生过程。这些数据还表明，ATM基因可能在B - CLL中报道的11号染色体q23异常中起作用，该异常也表征了一种侵袭性疾病。
